Human Vaccines & Immunotherapeutics

ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/khvi20

Immunotherapy and radiotherapy in melanoma: a

multidisciplinary comprehensive review

Luca Tagliaferri, Valentina Lancellotta, Bruno Fionda, Monica Mangoni,

Calogero Casà, Alessandro Di Stefani, Monica Maria Pagliara, Andrea
D’Aviero, Giovanni Schinzari, Silvia Chiesa, Ciro Mazzarella, Stefania
Manfrida, Giuseppe Ferdinando Colloca, Fabio Marazzi, Alessio Giuseppe
Morganti, Maria Antonietta Blasi, Ketty Peris, Giampaolo Tortora & Vincenzo
Valentini

To cite this article: Luca Tagliaferri, Valentina Lancellotta, Bruno Fionda, Monica Mangoni,
Calogero Casà, Alessandro Di Stefani, Monica Maria Pagliara, Andrea D’Aviero, Giovanni
Schinzari, Silvia Chiesa, Ciro Mazzarella, Stefania Manfrida, Giuseppe Ferdinando Colloca,
Fabio Marazzi, Alessio Giuseppe Morganti, Maria Antonietta Blasi, Ketty Peris, Giampaolo
Tortora & Vincenzo Valentini (2022) Immunotherapy and radiotherapy in melanoma: a
multidisciplinary comprehensive review, Human Vaccines & Immunotherapeutics, 18:3,
1903827, DOI: 10.1080/21645515.2021.1903827

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HUMAN VACCINES & IMMUNOTHERAPEUTICS
2022, VOL. 18, NO. 3, e1903827 (8 pages)
https://doi.org/10.1080/21645515.2021.1903827

MELANOMA IMMUNOTHERAPY SF – REVIEW

Immunotherapy and radiotherapy in melanoma: a multidisciplinary comprehensive

review
Luca Tagliaferria, Valentina Lancellottaa, Bruno Fionda a, Monica Mangonib, Calogero Casàa, Alessandro Di Stefanic,
Monica Maria Pagliarad, Andrea D’Avieroa, Giovanni Schinzarie,f, Silvia Chiesaa, Ciro Mazzarellaa, Stefania Manfridaa,
Giuseppe Ferdinando Collocaa, Fabio Marazzia, Alessio Giuseppe Morgantig, Maria Antonietta Blasid,f, Ketty Perisc,f,
Giampaolo Tortorae,f, and Vincenzo Valentinia,f
a
UOC Radioterapia Oncologica, Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico
Universitario A. Gemelli, IRCCS, Roma, Italy; bSezione di Radioterapia Oncologica, Dipartimento di Scienze Biomediche Sperimentali e Cliniche,
Università di Firenze, Florence, Italy; cUOC Dermatologia, Dipartimento di Scienze mediche e chirurgiche, Fondazione Policlinico Universitario
A. Gemelli, IRCCS, Roma, Italy; dUOC Oncologia Oculare, Dipartimento di Scienze dell'Invecchiamento, neurologiche ortopediche e della testa collo,
Fondazione Policlinico Universitario A. Gemelli, IRCCS, Roma, Italy; eUOC Oncologia Medica, Comprehensive Cancer Center, Fondazione Policlinico
Universitario A. Gemelli, IRCCS, Roma, Italy; fUniversità Cattolica del Sacro Cuore, Roma, Italy; gDipartimento di Medicina Specialistica, Diagnostica
e Sperimentale Settore Scientifico Disciplinare, Università di Bologna, Bologna, Italy

ABSTRACT ARTICLE HISTORY

Melanoma is an extremely aggressive tumor and is considered to be an extremely immunogenic tumor Received 29 December 2020
because compared to other cancers it usually presents a well-expressed lymphoid infiltration. The aim of this Revised 16 February 2021
paper is to perform a multidisciplinary comprehensive review of the evidence available about the combination Accepted 10 March 2021
of radiotherapy and immunotherapy for melanoma. Radiation, in fact, can increase tumor antigens visibility KEYWORDS
and promote priming of T cells but can also exert immunosuppressive action on tumor microenvironment. Melanoma; radiotherapy;
Combining radiotherapy with immunotherapy provides an opportunity to increase immunostimulatory radiation therapy;
potential of radiation. We therefore provide the latest clinical evidence about radiobiological rationale, radio­ immunotherapy
therapy techniques, timing, and role both in advanced and systemic disease (with a special focus on ocular
melanoma and brain, liver, and bone metastases) with a particular attention also in geriatric patients. The
combination of immunotherapy and radiotherapy seems to be a safe therapeutic option, supported by a clear
biological rationale, even though the available data confirm that radiotherapy is employed more for metastatic
than for non-metastatic disease. Such a combination shows promising results in terms of survival outcomes;
however, further studies, hopefully prospective, are needed to confirm such evidence.

Introduction
Melanoma is an extremely aggressive tumor accounting for
about 5% of all cancers and characterized by a variable incidence
depending on geographical and racial factors; in the past years,
there have been major biological therapeutic strategies investi­
gated including the targeting of BRAF, MEK, and KIT
inhibitors1. In particular, melanoma is considered to be an
extremely immunogenic tumor because compared to other can­
cers it usually presents a well-expressed lymphoid infiltration.2
For this reason, several monoclonal antibodies inhibiting dif­
ferent targets including anti-programmed cell death protein 1
(PD-1), anti-programmed death ligand-1 (PDL-1), and cytotoxic
T-lymphocyte associated protein 4 (CTLA-4) have been studied.3,4
The aim of this paper is to perform a multidisciplinary com­
prehensive review of the evidence available about the combination
of radiotherapy (RT) and immunotherapy (IT) for melanoma.
Radiobiological rationale
The response to IT depends on preexisting tumor infiltrate and
may be improved by RT, which is able to activate an antitumor
immune response. Moreover, IT has proven to synergize with
radiation-induced immune activation and to convert the immu­
nosuppressive microenvironment of a tumor into an in situ
vaccine,5 boosting the abscopal effect, which is defined as the
clinical observation of tumor responses outside the irradiated
field. Radiation causes an immunogenic cancer cell’s death,
resulting in release of damage-associated molecular pattern
molecules (DAMP) such as adenosine triphosphate (ATP) and
High Mobility Group Protein B1 (HMGB1) and in translocation
on the cancer cell surface of the “eat me signal” calreticulin that
promotes phagocytosis. Also, upregulation of MHC-I expression
on the tumor surface increases tumor antigen presentation.6 In
the cytosol, radiation-induced DNA fragments lead to activation
of the Stimulator of Interferon Genes (STING) that in turn
upregulate interferon type I (IFN-I), activating innate and adap­
tive immune responses.6 Radiation can increase tumor antigens
visibility and promote priming of T cells but can also exert
immunosuppressive action on tumor microenvironment.
Combining RT with IT provides an opportunity to increase
immunostimulatory potential of radiation, even though factors
influencing the final balance in immunomodulation are mostly

CONTACT Bruno Fionda bruno.fionda@yahoo.it UOC Radioterapia Oncologica, Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed
Ematologia, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Largo Agostino Gemelli, 8, Roma 00168, Italy.
© 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/),
which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.
e1903827-2 L. TAGLIAFERRI ET AL.
unknown. Clinical observations suggest a link with irradiated
site and strategy of treatment combination.6 Recent immunolo­
gical data showed that RT results in immune system enhance­
ment, and in particular, the role of dose per fraction is crucial: in
fact, doses above 12–18 Gy induce exonuclease Trex1, which
attenuates radiation-induced immunogenicity by degrading
cytosolic DNA.7
Techniques: external beam radiotherapy,
interventional radiotherapy, proton therapy
RT is rarely used to treat non-metastatic melanoma while it
plays an important role in metastatic disease.8 About 15% of
patients with melanoma have metastatic disease at diagnosis or
will develop metastatic disease during their illness.9
Many retrospective studies showed a significant median overall
survival (OS) benefit in patients who received RT combined with
IT compared to IT or RT alone.10–13 The optimal timing and the
toxicity profile for RT in this setting of anti-PD 1 therapy remain
unknown, and clinical experience related with this combination is
poor.10–16 However, several retrospective studied showed
a significant median OS benefit for patients who received IT
after RT10–16 or in combination10 compared to patients receiving
IT before or after 5 weeks from RT.11,13–17 Treatment with stereo­
tactic RT (SRS) as compared to external beam RT (EBRT) was also
a statistically significant predictor of improved OS.12,13 Finally, the
side effect profile of patients receiving RT combined with did not
appear to be different from that of patients receiving RT or IT
alone.11,13–17
Proton beam therapy (PBT) is becoming an alternative to
treat cancer patients undergoing RT. Preclinical and clinical
data have shown potential immunosuppressive mechanisms
associated with its dose distribution advantages. In vitro data
has shown that PBT and X-ray irradiation achieves similar
levels of survival of radiated melanoma cells. Still, only PBT
induces long-term inhibition of migration of melanoma cells.18
In vivo and clinical data for systemic tumor responses resulting
from association of protons and IT are limited.19
Only a few clinical papers have been published about the
association of interventional RT (IRT- brachytherapy) and IT.
The potential advantages to IRT over EBRT may be the high
conformal dose distribution and dose heterogeneity. The pre­
clinical study demonstrated that IRT induces an antitumor
immune response, thus enhancing IT.20 Only three studies
reported a combination of IRT and IT. Two of them implied
90 Y microspheres for liver metastases combined with either
dual checkpoint blockade or a chimeric antigen receptor-
modified T cell targeting the CEA antigen (NCT02913417,
NCT02416466). In another paper, the authors investigate the
addition of anti-PD-1 to standard chemoradiotherapy in
patients with advanced cervical cancer (NCT02635360).
Timing: pre, concomitant, post
Traditionally, the timing sequence between chemotherapy (CT)
and RT in solid tumors has been divided into sequential (either
neoadjuvant or adjuvant) or concomitant, in particular, the ratio­
nale for administering concomitant CT is mainly to obtain
a better local control enhancing the results of RT. On the contrary,
when combining IT and RT, the primary rationale for such
combination differs profoundly; in fact, RT administered triggers
locally and fosters the immune system to obtain an enhanced
systemic response.21,22 When considering combination therapy in
solid tumors including melanoma, several authors have proposed
to use “induction” IT before CT; such a strategy may be appealing
also for the combination of IT and RT.23
Concerning the combination of IT and RT, most clinical
experiences present in literature show that such combination
may be used before or after disease progression when the tumor
has managed to escape the immune system or during the induc­
tion, within a few days before or after the first dose of IT.24–30 For
this reason, we may analyze the results of the current evidence
dividing them into two main categories of timing combination:
(1) Combination of RT and IT after the tumor escapes the
immune system or post-escape radiotherapy (PER); in
this setting, there is no exact timing to define because
the use of RT depends on the time of the tumor escap­
ing the immune system surveillance.
(2) Combination of RT and IT during the induction phase
or peri-induction radiotherapy (PIR); regarding this
setting clinical experiences available in literature, there
are both prospective and retrospective experiences as
listed in Table 1 with irradiated sites classified according
to AJCC 8th edition.31
As can be seen from Table 1, the vast majority of clinical
data available in literature allows us to see how RT is employed
more for metastatic than for non-metastatic disease; the main
reason could be the fact usually surgery is the first choice of
treatment for primary lesions except for selected clinical set­
tings such as uveal melanoma.
Due to the radio-resistance of melanoma, very high doses
are needed to obtain a complete remission; for this reason, the
use of RT as alternative to surgery needs to be evaluated in
multidisciplinary discussion considering the location and the
treatment sequelae.
Locally advanced
Locally advanced melanoma includes unresectable stage IIIB,
IIIC, and IVM1a.32,33 Several local treatments are effective for
unresectable locally advanced melanoma.34 Nevertheless, data
about the combination of immune checkpoint inhibitors and
RT for locally advanced melanoma are limited.
Theurich et al. conducted a retrospective clinical study to test
the efficacy of the combination of local tumor treatment (RT or
electrochemotherapy or selective internal RT) and ipilimumab
in 45 advanced melanoma patients, 8 of them (17.7%) with stage
IIIC disease and 6 (13.3%) with stage IVM1A.35 Considering the
subjects without central nervous system metastases, OS was
117 weeks for patients treated with ipilimumab and local treat­
ment versus 46 weeks with ipilimumab alone (HR 0.41; 95% CI,
0.17–0.78, p = .0116). The addiction of radiation therapy to
ipilimumab allowed a better outcome irrespective of locally
advanced (stage IIIC+IVM1a) or distant organ metastatic dis­
ease (stage IVM1b+c) at multivariate analysis (HR 0.57, 95% CI
0.23–1.41, p = .23).35 Another retrospective study considered
 HUMAN VACCINES & IMMUNOTHERAPEUTICS e1903827-3

patients treated with peri-induction radiotherapy (PIR) and

Principal metastatic
ipilimumab.26 Among the 29 patients who underwent RT

M1a and M1d

M1a and M1d

M1b and M1c
irradiated site
between the first and the last dose of ipilimumab, 3 had unre­

M1b

M1d

M1a
M1c
sectable M0 or M1a disease. PIR and ipilimumab did not cause
unexpected rate of adverse events or detrimental effect on ipili­
mumab-induced survival benefit.
In a phase II trial, stereotactic body radiation therapy was
performed after the first nivolumab administration in 20
advanced melanoma patients.36 This trial enrolled seven
From 12 Gy in 2 fx to 24 Gy in 3 fx

From 18 Gy in 1 fx to 50 Gy in 4 fx

Median 36 Gy (range 20–60) and

From 18 Gy in 1 fx to 50 Gy in 25 fx

median fraction 5 Gy (range

patients (35%) with locally advanced disease. The overall
Dose and fractionation

response rate of 45% was similar to that obtained with nivo­

lumab alone in the historical controls, excluding an abscopal
effect in these patients’ population. Prospective trials are
warranted to establish the role of the combination of RT
30 Gy in 10 fx

30 Gy in 10 fx

30 Gy in 10 fx

1.8–8) and IT for locally advanced melanoma. Two phase

I (NCT01557114 and NCT01996202) and one phase II
(NCT01689974) prospective studies considered locally
advanced melanoma patients treated with the combination
of ipilimumab and radiation therapy. All these studies com­
pleted the enrollment period. The results will provide further
Median induction to PIR time
Between 0 and +16 weeks

Between −11 and +7 days

data on safety and efficacy of immuno-radiation for locally

Between 0 and +28 days

Between −54 and 0 days

Between 0 and +5 days

Between 0 and +5 days

Between −9 and 0 days

advanced melanoma patients.

Systemic disease
Brain metastases
Brain metastases occur with an incidence of 10–40% in advanced
stage melanoma37 and are associated with significant morbidity
and account for 20–54% of reported deaths from melanoma.38
18 patients
22 patients
47 patients
22 patients
27 patients

11 patients
4 patients

The standard of care remains the resection of large symptomatic

PIR

lesions or the RT, followed by systemic therapy. SRT allows for

a local control (LC) rate up to 90% and a median OS of
5–11 months.39,40 Recently, with the introduction of ipilimumab,
the interest about the synergistic effect has increased. Local RT can
increase the permeability of the blood–brain barrier,41 can prime
pembrolizumab

pembrolizumab

antitumor immunity through release of tumor antigens,42 and

Drug used

Pembrolizumab
Nivolumab or

Nivolumab or

alter the tumor proinflammatory microenvironment.43

Ipilimumab
Ipilimumab
Ipilimumab
Ipilimumab
Table 1. Summary of main studies available in literature about PIR in melanoma.

Unfortunately, results are often contradictory. Some studies

have reported the benefit of OS or LC in patients who receive
ipilimumab and RT,11,17,44–47 with a prognosis becoming at least
similar to that of patients without brain metastaes. Some other
studies have shown no difference in terms of LC or OS,12,48 and
Type of study
Retrospective

Retrospective

Retrospective

Retrospective

Retrospective

others reported a survival benefit in case of SRT before

Prospective

Prospective

ipilimumab.14,16 Regarding the toxicity, several authors did not

observe an increase of radiation necrosis, hemorrhage, or other
toxicity in cases of combination of RT with IT.9,11,12,16,44,48
2013
2015
2015
2016
2016

2019

2019
Year

Liver metastases
The frequency of liver metastases in patients who present with
stage IV melanoma disease is 15–20%, with a 5-year survival of
Twyman-Saint Victor et al.

less than 10%.49 Several studies have reported evidence of the

immunogenic effect with local irradiation of liver metastases
who receive immune checkpoint inhibitors (ICIs).35,50,51 The
Chandra et al.
Hiniker et al.

efficacy of PIR and ipilimumab in metastatic melanoma on OS

Liniker et al.
Barker et al.

Kato et al.

Kim et al.

outcomes has been reported in prospective and retrospective

Author

studies, with a median OS of 19 months (4–39 months).26

Immune-related-adverse events (ir-AEs) were similar to those
e1903827-4 L. TAGLIAFERRI ET AL.

produces by use of ipilimumab alone.52 Also, the combination Ocular melanoma

between anti PD-L1 and RT would seem to be effective and safe.53
Melanoma of the ocular region comprises about 5% of all patients
The best dose/fractionation regimen is still a matter of debate.
with melanoma and includes conjunctival melanoma and uveal
Patients receiving a higher dose-per-fraction (>3/5 Gy/fx) have
melanoma; these subtypes of ocular melanoma have distinct
shown better clinical outcomes.54 Concerning the timing, sequen­
biological features, which should be taken into consideration
cing, and interval, some authors did not identify a significant
when making treatment decisions.79 The tumor mutational bur­
difference in the rates of ir-AEs.52,53 Although the toxicity increase
den is hypothesized to correlate with the neoantigen load and thus
could be associated to the temporal proximity of the two
the immunogenicity of tumors. Currently, it seems to be a useful
treatments.52 Gabani et al.55 observed that the addition of SBRT
predictive biomarker for response to ICIs across tumor entities.80
to ICIs improved OS in patients with soft tissue metastases at least
While conjunctival melanomas, as well as cutaneous, are asso­
30 days before starting IT. However, very few liver melanoma
ciated with ultraviolet sun exposure and display a subsequent
metastatic patients have been included in these studies. Future
extremely high mutational burden with up to 100 mutation per
clinical trials should consider the site, the IT agents, and the
megabase,81 in uveal melanoma the mutational load is among the
timing of RT to select patients who could benefit from their
lowest of all cancer types of around 0.5 per Mb sequence.80,82 In
synergy.
fact, uveal melanoma arises in the eye in an immune-privileged
environment that possesses inhibitory properties against both the
Bone metastases innate and the adaptive immunity system.83 This may protect
cancer cells not only at the site of the primary tumor but also
Bone metastases are a common site of melanoma metastatic
may hamper a successful antitumor immune response in other
spread after lung, liver, and brain, occuring in about 5–15% of
sites of the body and thus contribute to ICIs blockade failure in
patients49,56,57 with a prevalent involvement of the axial skeleton.
uveal melanoma.84 For local treatment, IRT with plaques and
The prognosis is poor and almost similar to that of patients
PBT, represent the gold standard of care; however, RT has not
developing brain or liver metastases. Five-year survival is approxi­
yet been associated to IT, even in the presence of negative prog­
mately 27%58 with a median survival of 10.7 months.59 Worst
nostic factors, because the biological characteristics of UM do not
prognosis factors for survival are male patients, melanoma of the
justify a combination of RT with IT at the moment.
trunk, high LDH levels at bone meatstases diagnosis, evidence of
The management of metastatic uveal melanoma is challen­
≥3 metastatic sites as well as ≥5 bone meatstases.59 Bone meat­
ging. Although it is characterized by some immune infiltrates,
stases can cause severe and debilitating effects including pain,
the use of ICIs for metastases has shown limited response in
spinal cord compression, hypercalcemia, and pathological frac­
comparison to cutaneous melanoma.85 Recently, an excep­
ture. RT provides symptomatic improvement of 50–86%
tional immune response in UM patients harboring MBD4
patients60–63 and response improves with total doses of
mutations has been described. This evidence of selected groups
30 Gy.64–66 Since the RT plays a role in the palliative treatment
of UM that could benefit from IT86 in addition to RT or CT
of metastatic disease, its use in combination with IT has been
aimed at modulating and enhancing the antitumoral immune
explored,44,55,67,68 indicating a possible improvement in clinical
response in uveal melanoma opens new perspectives for the
outcomes.35,60,69 RT dose and fractionation may also play an
future. Wide surgical excision followed by cryotherapy to the
important role in maximizing induction of immune
surgical margins is the first-line treatment for conjunctival
response24,70 even if confirmation of survival benefit from large
melanoma, supplemented with topical chemotherapy or local
prospective studies is lacking.25 Analysis of retrospective large
RT due to the high recurrence rates.87 Adjuvant RT treatments
database on the patterns of care of patients with bone meatstases
include EBRT, PBT, and IRT. Despite local adjuvant treatment,
receiving IT highlights a better survival with the integration of
the risk of local recurrence is high (30–60%), nodal involve­
palliative RT to IT (16 months, 95% CI = 10.4–20.7);59 further­
ment occurs in 15% of patients, and finally about 20–30% of
more, the combination of hypofractionated RT (>5 Gy/fx) and IT
patients develop distant metastases.79 Given genetic similarities
demonstrated a significantly higher survival probably due to its
to cutaneous melanoma, in a few case reports/case series,
immunogenic effect.60,71,72
immune-based therapies have shown durable responses to
In these recent years, IT’s introduction has changed the
treatment after excision and adjuvant RT, in locally advanced
natural history of melanoma and its therapeutic landscape
or metastatic conjunctival melanoma.88,89 While clinical trials
with a greater proportion of oligometastatic presentation the­
for cutaneous melanoma and few studies for mucosal mela­
oretically suitable for SBRT72 to improve the therapeutic ratio
noma have reported the results of combined RT and anti-PD-1
through increased tumor cell killing while maintaining stable
therapy, because of its rarity no study has been conducted to
or decreased toxicity.52,73–75
compare the role of RT with IT versus RT alone, in the
A more significant number of fractions and a generally
adjuvant treatment of conjunctival melanoma.
larger area of treatment with CFRT (≤5 Gy/fx) may lead to
more substantial lymphopenia, which can hinder tumor cell
eradication by cytotoxic T lymphocytes,76–78 and this could
Elderly patients: clinical management
partially justify a little benefit from the combination with IT.59
Some factors that could influence treatment outcomes have The rapid expansion of the aging population is associated with an
yet to be identified in future clinical trial incorporating RT for increase in skin cancer and melanoma incidence. This scenario
BM, such as the best temporal sequencing of RT/IT, and which represents one of the most significant challenges in the manage­
RT dose-fractionation would be more “immunogenic.” ment of this cancer.90 On the one hand, it is increasingly crucial

for the effective treatment of melanoma.91 On the other hand,
aging is associated with a dysregulation of the immune system
(immunosenescence and inflammaging), which could alter the
effectiveness of the treatments themselves.92–94 It is in the older
cancer patient that the real personalization of treatments takes
place. Factors related to the patient him/herself rather than cancer
must be considered in the therapeutic choice. Compliance linked
to the social network, polypharmacy, multimorbidity, frailty,
active life expectancy, and the physiological changes related to
aging are the main factors to consider when choosing treatment in
the elderly patient.95–98 Older cancer patients often do not have
a social network able to cover the indications or problems relating
to treatments. In these cases, it is important to avoid starting
a treatment that patients may not complete due to external factors.
There is need for a shift of mindset from the idea of comorbidities
(as the presence of multiple pathologies in addition to the main
one) to the holistic idea of several diseases present (acute and
chronic) in the patient, each of which is able to influence the
others and the prognosis in the patient. Frailty, the basis of
modern geriatrics, is the concept of a homeostatic mechanism
for which a frail patient, if subjected to stress (such as cancer
treatments), can precipitate in a state of disability. Therefore, it is
essential to identify the frail patient from the fit one before making
any therapeutic choice. Hypothesize an assessment of the sarco­
penia, closely linked to more significant toxicity to treatments, and
customize therapies based on these data.99 For active life expec­
tancy, any treatment choice in the older patient should consider
the patient’s life expectancy and quality of life. These two factors
are not related to the chronological age data but rather to the
patient’s physical and cognitive performance.96
Finally, it is necessary to remember that physiologically the
body has changes related to aging that impact drugs’ pharmaco­
dynamics and pharmacokinetics.97 Thus, before any decision, it is
essential to carry out a geriatric assessment of the patient (through
a screening test or a comprehensive geriatric assessment) in order
to be able to carry out a truly personalized treatment.
Conclusions
The combination of IT and RT seems to be a safe therapeutic
option, supported by a clear biological rationale, even though the
available data confirm that RT is employed more for metastatic
than for non-metastatic disease. Such a combination shows pro­
mising results in terms of survival outcomes; however, further
studies, hopefully prospective, are needed to confirm such
evidence.
Disclosure of potential conflicts of interest
All authors declare no potential conflicts of interest.
ORCID
Bruno Fionda http://orcid.org/0000-0003-3368-1810
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